Total synthesis of (-)-α-Kainic acid via chirality transfer through Ireland-Claisen rearrangement

Article abstract of DOI:10.1021/jo400001t

The total synthesis of (-)-α- Kainic acid is accomplished using a linear strategy involving Noyori asymmetric reduction and chirality transfer through Ireland-Claisen rearrangement as key steps.

Full text of DOI:10.1021/jo400001t

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Note
Total Synthesis of (-)-alpha- Kainic acid via Chirality
Transfer through Ireland – Claisen Rearrangement
Naredla Kesava Reddy, and Srivari Chandrasekhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400001t • Publication Date (Web): 07 Mar 2013
Downloaded from http://pubs.acs.org on March 12, 2013
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Total Synthesis of (ꢀ)ꢀαꢀ Kainic acid via Chirality Transfer through Ireland –
Claisen Rearrangement
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Naredla Kesava Reddy and Srivari Chandrasekhar*
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Division of Natural Products Chemistry, CSIRꢀIndian Institute of Chemical
Technology, Hyderabad, India 500 007
srivaric@iict.res.in
Abstract: The total synthesis of (ꢀ)ꢀαꢀ Kainic acid is accomplished using a linear strategy
involving Noyori asymmetric reduction and chirality transfer through IrelandꢀClaisen
rearrangement as key steps.
(ꢀ)ꢀαꢀKainic acid is isolated from Japanese marine alga Digenia simplex 1953 later
found in related algae as well.1 (ꢀ)ꢀαꢀkainic acid (1), domoic acid (2) and acromelic acid B (3) are
categorized under the kainoid family of non proteinogenic amino acids. These amino acids have
the same relative stereochemistry i.e. transꢀC2/C3, cisꢀC3/C4 which is crucial for its biological
activity.
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(ꢀ)ꢀαꢀKainic (1) acid is characterized as a five membered pyrrolidine skeleton
with an isopropenyl group, methylene carboxyl and carboxyl group appended onto it in a
synꢀanti fashion. Compound 1 has been widely used as an experimental tool, due to its
neuroexcitotoxic and epileptogenic properties in screening of CNS disorders such as
Alzheimer’s disease2 and epilepsy3 in animal models. It is also reported that Digenia
simplex exhibited antihelminthic properties in traditional Japanese folklore. The structure
of kainic acid can be envisaged as a conformationally restricted analogue of the
neurotransmitter glutamic acid and is also confirmed by its neuroexcitation activity
leading to specific neuronal death in brain.3b The interesting biological properties and the
challenging structural complexity with three contiguous chiral stereo centers has attracted
the attention of organic chemists. To date, over 30 total syntheses of (ꢀ)ꢀαꢀkainic acid and
its congeners have been reported in literature using diverse synthetic strategies.4 Very
recently Gallos and coꢀworkers have compiled a review on recent approaches.5 Most of
the synthetic strategies revolved around cycloadditions,4h,4l,4x eneꢀreaction,4q radical
cyclisation,4u PausonꢀKhand reaction4r and DielsꢀAlder reaction4o as key reaction for the
construction of C3ꢀC4 cis stereochemistry. Furthermore the asymmetric carbon bearing ꢀ
COOH group (C2) was generally achieved using chiral starting materials. In continuation
of our interest in the synthesis of pyrrolidine class of natural products and marine
originated bioactive molecules,6 herein we report the total synthesis of 1 using an
altogether different strategy involving IrelandꢀClaisen rearrangement for C3ꢀC4 cis
stereocenters7 and Sharpless asymmetric epoxidation as key reactions in installing the
chirality at C2.
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Scheme 1. Retrosynthesis for (ꢀ)ꢀαꢀKainic Acid (1)
As delineated in retrosynthetic planning (Scheme 1), we envisaged a 5ꢀexoꢀtet
cyclization of azido epoxy alcohol 4 which in turn was planned to be synthesized through
chirality transfer from allyl ester 6 involving IrelandꢀClaisen rearrangement via homoallylic
alcohol 5. Compound 6 could in turn be obtained from ynone 7. By applying IrelandꢀClaisen
rearrangement it is also possible to synthesize other kainoid family of natural products.
The differentially protected ynone 78 was subjected to Noyori asymmetric reduction
conditions to obtain secondary propargyl alcohol 8 in 83% yield and with >95% ee.9 The
classical reduction of triple bond to (E)ꢀolefin was achieved using RedꢀAl to generate allyl
alcohol 9 in 86% yield. The next task of introducing the appendage for IrelandꢀClaisen
rearrangement was accomplished by coupling of alcohol 9 with 3ꢀmethylꢀ3ꢀbutenoic acid10 under
DCCꢀDMAP conditions. The obtained ester 6 was subjected to LiHMDS/TMSCl for a smooth
sigmatropic reaction with an excellent chirality transfer followed by the treatment with
diazomethane provided 10 in 79% yield over two steps.11 Having installed the desired arms with
right chirality, the next challenge was to construct the pyrrolidine ring. This process commenced
with a DIBALꢀH reduction of 10 to generate the homoallylic alcohol 5 (86% yield) which was
protected as acetate 11 in 95% yield.
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O
OH
Red-Al 65wt-
OH
Noyori (S,S)
HCO2H-Et3N (1:1),
PMBO
PMBO
% in toluene
PMBO
CH2Cl2, 0 oC
to rt, 1 h, 86%
OBn
OBn
OBn
rt, 83%, 95% ee
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O
O
(i) LiHMDS, TMSCl
3-methyl-3-
butenoic
THF, -78 oC to rt,15 h
O
DIBAL-H
MeO
PMBO
(ii)CH2N2, Et2O, 0 oC,
0.5 h, 79% (2 steps)
CH2Cl2, 0 oC
1 h, 86%
PMBO
DCC, DMAP
CH2Cl2, 0 oC to
rt, 12 h, 80%
OBn
OBn
6
10
O
(Ac)2O,
HO
DDQ
DMAP, Et3N
O
PMBO
CH2Cl2, 0 oC to
rt, 5 h, 95%
CH2Cl2, H2O (3:1)
0 oC to rt, 0.5 h, 89%
PMBO
OBn
OBn
5
11
O
O
Ts
Ti (i-OPr)4, (-)-
Ph
N
O
O
DET, TBHP
O
Ru
N
HO
CH2Cl2, -20 oC
5 h, 82%
Ph
HO
OBn
OBn
Ts
Noyori (S,S)
12
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Scheme 2. Synthetic of epoxy alcohol 13
The pꢀmethoxybenzyl group was knocked down oxidatively using DDQ to produce allyl
alcohol 12 (89% yield), a desirable building block for Sharpless asymmetric epoxidation. The
asymmetric epoxidation using (ꢀ) DET and TBHP produced epoxy alcohol 13 in 82% yield as an
exclusive diastereomer (Scheme 2). The silylation of 13 to14 was uneventful. The deacetylation
and azidation were achieved using K2CO3/MeOH followed by Mitsunobu reaction to generate
epoxy azide 15 albeit in low yields (45% over two steps). The removal of silyl group was
mediated by TBAF to furnish azido epoxy alcohol 4. The pyrrolidine ring was constructed in one
stroke by reduction of 4 with TPP in THF, wherein azide was reduced to amine which further
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underwent a facile 5ꢀexoꢀtet cyclisation12 and was in turn trapped as carbamate 16 in 68% yield
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5
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(Scheme 3).
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O
(i) K2CO3, Me OH,
-10 oC, 1 h
TBDMS-Cl,
imidazole
N3
O
O
O
13
10
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TBSO
TBSO
CH2Cl2, 0 oC
to rt, 2 h, 94%
OBn
OBn
(ii) DIAD, DPPA, TPP
THF, 0 oC to rt, 10 h,
45 % (two steps)
14
15
OBn
OH
(i) NaIO4, THF/H2O,
(2:1), 0 oC, 1 h
(i) TPP, THF,
H2O (cat), rt, 48 h
TBAF, THF,
0 oC, 2 h, 90%
N3
O
N
H
HO
HO
OBn
(ii) (BOC)2O, Et3N
rt, 12 h, 68%
(ii) NaBH4, CH3OH,
0 oC,10 min, 87%
(two steps)
O
O
16
4
OBn
OH
OH
O
(i) Jones reagent,
acetone, 0 oC to
rt, 15 min
Li-naphthalene
OH
OH
N
OH
THF, 0 oC,
0.5 h, 81%
(ii) TFA, CH2 Cl2
0 oC to rt, 3 h, 62%
N
O
N
O
H
O
O
O
17
18
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Scheme 3. Completion of Total Synthesis of (ꢀ)ꢀαꢀKainic Acid
The resultant vicinal diol functionality in 16 was oxidatively cleaved with NaIO4 and the
resultant aldehyde was subjected to NaBH4 reduction to produce 17 which has all the necessary
substituents stitched on the pyrrolidine ring with requisite stereogenic centers. The Liꢀ
naphthalide mediated debenzylation yielded the diol 18 which underwent a smooth oxidation
with Jones reagent followed by Bocꢀdeprotection to realize (ꢀ)ꢀαꢀkainic acid 1 in (62% yield
over two steps). This compound exhibited all the desired spectral data, fully identical to the
reported ones.4r
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In summary, the natural (ꢀ)ꢀαꢀkainic acid has been synthesized involving chirality transfer
through sigmatropic rearrangement and 5ꢀexoꢀtetꢀcyclisation with complete regio and
stereocontrol.
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Experimental Section
General
NMR spectra were recorded in CDCl3 or D2O solvent on 300, 400 or 500 MHz spectrometers.
Chemical shifts are reported in parts per million (ppm). 1H NMR spectra were recorded at 300, 400
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or 500 MHz and chemical shifts are referenced to TMS (
δ
= 0.0) as internal standard. C NMR
spectra were recorded at 75, 100 or 125 MHz and chemical shifts are referenced to CDCl3 (δ =
77.0). FTIR spectra were recorded on KBr thin films. Optical rotations were measured on an
digital polarimeter by using a 2ꢀmL cell with a path length of 1 dm. HRMS were recorded on an
LCꢀESIꢀQTOFꢀmass spectrometer. All the reagents and solvents were of reagent grade and used
without further purification unless otherwise stated. Technicalꢀgrade EtOAc, hexanes, CHCl3 and
MeOH used for column chromatography were distilled before use. THF, when used as a solvent
for reactions, was freshly distilled from sodium benzophenone ketyl. Column chromatography was
carried on silica gel (60–120 mesh) packed in glass columns. All the reactions were performed
under N2 in flameꢀ or oven dried glassware with magnetic stirring.
Experimental procedures
6ꢀ(Benzyloxy)ꢀ1ꢀ(4ꢀmethoxybenzyloxy)hexꢀ3ꢀynꢀ2ꢀone (7)
To a solution of alkyne (5.0 g, 31.2 mmol) in THF (62 ml) was added nꢀBuLi (15 ml, 37.5 mmol,
2.5 molar) at ꢀ78oC. After stirring for 2 h a solution of weinreb amide (8.9 g, 37.5 mmol) in THF
(38 ml) was added slowly to it. Stirring continued for 20 min at ꢀ78oC and for 2 h at 0oC and then
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the mixture was quenched with saturated NH4Cl solution. The mixture was extracted with
EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by silicagel chromatography (1:10 EtOAc/hexanes) to afford
7.03 g alkynone 7 (67%) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.38ꢀ7.24 (m, 7H),
6.88 (d, J = 8.3 Hz, 2H), 4.54 (d, J = 4.5 Hz, 4H), 4.16 (s, 2H), 3.79 (s, 3H), 3.61 (t, J = 6.7 Hz,
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2H), 2.67 (t, J = 6.7 Hz, 2H); C NMR (CDCl3, 75 MHz): δ 184.5, 159.4, 137.5, 129.6, 128.4,
127.7, 127.6, 113.8, 93.7, 79.1, 75.3, 73.0, 66.8, 65.1, 55.1, 20.5; IR (KBr) vmax: 3031, 2932,
2863, 1728, 1710, 1611, 1249 cmꢀ1; HRMS: Calcd for C21H23O4 (M+H)+: 339.1591, found:
339.1599.
(S)ꢀ6ꢀ(Benzyloxy)ꢀ1ꢀ(4ꢀmethoxybenzyloxy)hexꢀ3ꢀynꢀ2ꢀol (8)
To a solution of (S,S) Noyori catalyst (376 mg, 0.05 mmol) in 10 ml CH2Cl2 was added a
solution of alkynone 7 (4 g, 11.8 mmol) in 24 ml of formic acid triethylamine mixture (1:1). The
resultant mixture was stirred for 6 h, and then water 10 ml was added to dilute and extracted with
CH2Cl2. The combined organic layers were washed with NaHCO3, dried over Na2SO4,
concentrated under reduced pressure to afford crude oil. The crude product was purified by silica
gel chromatography eluting with (EtOAc/hexanes 3:10) to give propargyl alcohol 8 (3.3 g, 83%)
as a colorless oil. [α]20 D −0.83 (c 0.6, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.34ꢀ7.24 (m, 7H),
6.88 (d, J = 7.9 Hz, 2H), 4.57ꢀ4.49 (m, 5H), 3.81 (s, 3H), 3.62ꢀ3.46 (m, 4H), 2.53 (td, J = 6.7 Hz,
13
2H); C NMR (CDCl3, 75 MHz) δ 159.2, 137.8, 129.6, 129.3, 128.2, 127.5, 113.7, 82.8, 78.8,
73.4, 72.8, 72.7, 68.0, 61.6, 55.1, 20.0; IR (KBr) vmax: 3430, 3063, 2923, 2860, 1612, 1513,
1248 cmꢀ1; HRMS: Calcd for C21H24O4Na (M+Na)+: 363.1567, found: 363.1559.
(S, E)ꢀ6ꢀ(Benzyloxy)ꢀ1ꢀ(4ꢀmethoxybenzyloxy)hexꢀ3ꢀenꢀ2ꢀol (9)
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RedꢀAl® (5.4 mL of a 65% w/w solution in toluene, 17.6 mmol) was added drop wise to a stirred
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5
6
o
solution of alkyneol 8 (3 g, 8.8 mmol) in dry CH2Cl2 (25 ml) at 0 C under nitrogen. The
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8
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reaction mixture was stirred at room temperature for 1 h, and then quenched by drop wise
addition of saturated aqueous potassium sodium tartrate. The mixture was vigorously stirred for
0.5 h and then filtered under vacuum. The filter residues were exhaustively washed with CH2Cl2,
the layers separated and the organic phase dried (Na2SO4) and concentrated. The viscous oil
obtained was purified by chromatography eluting with EtOAc / hexanes (3:10) to give alcohol 9
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1
(2.59 g, 86%) as a colorless oil. [α]20 D – 6.71 (c 2.92, CHCl3); H NMR (CDCl3, 500 MHz) δ
7.34ꢀ7.22 (m, 7H), 6.87 (d, J = 7.9 Hz, 2H), 5.78 (m, J = 14.9 Hz, 1H), 5.5 (dd, J = 15.9 Hz, 1H),
4.49 (m, 4H), 4.27 (br, 1H), 3.79 (s, 3H), 3.5 (t, J = 6.9 Hz, 2H), 3.46 (dd, J = 8.99 Hz, 1H), 3.32
(t, J = 6.9 Hz, 2H), 2.49 (br, 1H), 2.35 (q, J = 6.9 Hz, 2H) ; 13C NMR (CDCl3, 75 MHz) δ 159.2,
138.2, 130.0, 129.8, 129.7, 129.3, 128.2, 127.5, 127.4, 113.7, 73.8, 72.9, 72.8, 71.1, 69.4, 55.1,
32.7; IR (KBr) vmax : 3433, 3030, 2930, 2858, 1612, 1513, 1247 cmꢀ1; HRMS: Calcd for
C21H26O4Na (M+Na)+: 365.1723, found: 365.1701.
(S, E)ꢀ6ꢀ(Benzyloxy)ꢀ1ꢀ(4ꢀmethoxybenzyloxy)hexꢀ3ꢀenꢀ2ꢀyl 3ꢀmethylbutꢀ3ꢀenoate (6)
To a solution of alkenol 9 (2 g, 342 mmol) in CH2Cl2 (35 mL) were added 3ꢀmethylꢀ3ꢀbutenoic
°
acid (760 mg, 7.6 mmol), DMAP (214 mg, 1.75 mmol) and DCC (1.44 g, 7.01 mmol) at 0 C.
The reaction was stirred for 12 h at room temperature followed by dilution with hexane. The
generated white precipitate was removed by filtration through celite. The filtrate was
concentrated and residue was purified by column chromatography on silica gel (EtOAc/hexanes
1:9) to give 6 (1.98 g, 80%) as an oil. [α]20D −15.9 (c 1, CHCl3); 1H NMR (CDCl3, 300 MHz): δ
7.36ꢀ7.22 (m, 7H), 6.87 (d, J = 7.7 Hz, 2H), 5.8 (dt, J = 14.4 Hz, 1H), 5.53 (m, 2H), 4.9 (s, 1H),
4.87 (s, 1H), 4.5 (m, 4H), 3.79 (s, 3H), 3.58ꢀ3.48 (m, 4H), 3.06 (s, 2H), 2.37 (q, J = 6.6 Hz, 2H),
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1.8 (s, 3H); 13C NMR (CDCl3, 75 MHz): δ 170.3, 159.0, 138.4, 138.2, 131.6, 129.9, 129.0,
128.2, 127.4, 126.7, 114.4, 113.6, 73.0, 72.7, 72.5, 71.0, 69.2, 55.0, 43.5, 32.6, 22.3; IR (KBr)
vmax : 3060, 3031, 2918, 2852, 1733 cmꢀ1; HRMS: Calcd for C26H36NO5 (M+NH4)+: 442.2565,
found: 442.2565.
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(2S, 3R, E)ꢀMethyl 3ꢀ(2ꢀ(benzyloxy)ethyl)ꢀ6ꢀ(4ꢀmethoxybenzyloxy)ꢀ2ꢀ(propꢀ1ꢀenꢀ2ꢀyl)hexꢀ4ꢀ
enoate (10)
To a stirred solution of ester 6 (1.9 g, 4.48 mmol) in dry THF (45 mL) and TMSCl (1.2 ml, 8.9
°
mmol) was added. After the mixture was cooled to –78 C, LiHMDS (6.7 mL, 1M in THF, 6.7
mmol) was slowly added. The reaction was slowly warmed to room temperature and stirred for
15 h. It was acidified to pH 2ꢀ3 with 1N HCl aqueous solution and extracted with EtOAc twice.
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The
crude acid was taken to next step without purification. Acid was dissolved in to dry ether and
°
treated with ethereal solution of diazomethane at 0 C. After stirring the mixture for 0.5 h,
aqueous NH4Cl solution was added and extracted with EtOAc. The combined organic layers
were dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel hexanes/EtOAc 8:2 to give 10 (1.55 g, 79%)
1
for two steps. [α]20D +25.30 ( c 1.0, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.35ꢀ7.20 (m, 7H),
6.87 (d, J = 8.6 Hz, 2H), 5.61ꢀ5.50 (dt, J = 15.4 Hz, 1H), 5.3 (dd, J = 15.4 Hz, 1H), 4.88 (d, J =
6.7 Hz, 2H), 4.46 (q, J = 11.8 Hz, 2H), 4.35 (q, J = 11.5 Hz, 2H), 3.9 (m, 2H), 3.80 (s, 3H), 3.67
(s, 3H), 3.45 (m, 2H), 3.03 (d, J = 10.5 Hz, 1H), 2.76 (qd, J = 10.1 Hz, 2.6 Hz, 1H), 1.84ꢀ1.73
(m, 1H), 1.71 (s, 3H), 1.54ꢀ1.40 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 172.9, 159.0, 141.3,
138.4, 133.6, 130.3, 129.3, 128.7, 128.2, 127.6, 127.4, 115.5, 113.7, 72.7, 70.8, 69.8, 67.9, 58.4,
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55.2, 51.8, 39.8, 32.8, 19.8; IR (KBr) vmax : 2946, 2855, 1734, 1513, 1247cmꢀ1; HRMS: Calcd for
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C27H38NO5 (M+NH4)+: 456.2744, found: 456.2733.
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(2S, 3R, E)ꢀ3ꢀ(2ꢀ(Benzyloxy)ethyl)ꢀ6ꢀ(4ꢀmethoxybenzyloxy)ꢀ2ꢀ(propꢀ1ꢀenꢀ2ꢀyl)hexꢀ4ꢀenꢀ1ꢀol
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(5)
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A solution of methyl ester 10 (1.5 g, 3.42 mmol) in CH2Cl2 (35 mL) was cooled in 0 C and
treated drop wise with DIBALꢀH (3.88 mL, 6.84 mmol, 25% in toluene). The reaction mixture
°
was stirred at 0 C for 1 h and then quenched with saturated aqueous potassium sodium tartrate.
The biphasic mixture was washed with CH2Cl2. The combined organic layers washed with H2O
and brine, dried over (Na2SO4) and concentrated under reduced pressure. The residue was
purified by flash silica gel column chromatography (hexanes/EtOAc, 7:3) which gives alcohol 5
(1.4 g, 86%) as an oil. [α]20 −25.30 (c 1.0, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.34ꢀ7.20
1
D
(m, 7H), 6.87 (d, J = 8.3 Hz, 2H), 5.55ꢀ5.33 (m, 2H), 4.94 (s, 1H), 4.80 (s, 1H), 4.46 (q, J = 11.3
Hz, 2H), 4.37 (q, J = 12.0 Hz, 2H), 3.91 (m, 2H), 3.70 (dd, J = 10.5 Hz, 1H), 3.56 (t, J = 10.5
Hz, 1H), 3.51ꢀ3.35 (m, 2H) 2.40ꢀ2.21 (m, 2H), 1.86 (m, 1H), 1.68 (s, 3H), 1.60 (br, 1H), 1.45 (m,
1H); 13C NMR (CDCl3, 75 MHz): δ 159.0, 144.1, 138.3, 135.0, 130.4, 129.2, 128.3, 127.8,
127.7, 127.5, 114.9, 113.7, 72.9, 70.0, 68.0, 62.0, 55.2, 53.9, 39.2, 32.1, 20.1; IR (KBr) vmax
:
3454, 3067, 2935, 2858, 1612, 1513, 1248 cmꢀ1; HRMS: Calcd for C26H38NO4 (M+NH4)+:
428.2795, found: 428.2779.
(2S, 3R, E)ꢀ3ꢀ(2ꢀ(Benzyloxy)ethyl)ꢀ6ꢀ(4ꢀmethoxybenzyloxy)ꢀ2ꢀ(propꢀ1ꢀenꢀ2ꢀyl)hexꢀ4ꢀenyl
acetate (11)
To a solution of alcohol 5 (1.2 g, 2.9 mmol) in anhydrous dichloromethane (20 mL) cooled at 0
oC were added dry TEA (2.0 mL, 14.6 mmol) followed by DMAP (5 mol %). Acetic anhydride
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(0.85 mL, 8.7 mmol) was added dropwise and the reaction was stirred at the room temperature
for 5 h. The mixture was diluted with dichloromethane (20 mL) and washed with water (2 x 10
mL), brine and dried over anhydrous Na2SO4. Evaporation of the solvent under reduced pressure
yielded the crude product which was purified by flash column chromatography on silica gel
using EtOAc/hexanes as eluent to afford acetate 11 as a oil (1.19 g) 95% yield. [α]20D −18.10 (c
1.16, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.37ꢀ7.19 (m, 7H), 6.88 (d, J = 8.3 Hz, 2H), 5.58ꢀ
5.36 (m, 2H), 4.85 (s, 1H), 4.71 (s, 1H), 4.52ꢀ 4.34 (m, 4H), 4.23ꢀ4.03 (m, 2H), 3.95ꢀ3.90 (m,
2H), 3.80 (s, 3H), 3.52ꢀ3.35 (m, 2H), 2.42 (m, 2H), 2.02 (s, 3H), 1.94ꢀ1.80 (m, 1H), 1.68 (s, 3H),
1.57ꢀ1.42 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 170.9, 159.0, 143.4, 138.4, 134.3, 130.4,
129.2, 128.3, 128.2, 127.5, 127.4, 114.0, 113.7, 72.8, 71.0, 70.0, 68.1, 64.6, 55.1, 49.7, 39.6,
32.2, 20.99, 20.90; IR (KBr) vmax : 2922, 2852, 1736, 1511, 1239 cmꢀ1; HRMS: Calcd for
C28H36O5Na (M+Na)+: 475.2455, found: 475.2485.
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(2S, 3R, E)ꢀ3ꢀ(2ꢀ(Benzyloxy)ethyl)ꢀ6ꢀhydroxyꢀ2ꢀ(propꢀ1ꢀenꢀ2ꢀyl)hexꢀ4ꢀenyl acetate (12)
To a solution of acetylated compound 11 (1.1 g, 2.43 mmol) in a mixture of CH2Cl2 (9 mL) and
water (3 mL), DDQ (1.1 g, 4.89 mmol) was added at 0 °C. After 30 min, the reaction mixture
was warmed to room temperature and stirred for an additional 30 min before it was diluted with
CH2Cl2 (10 mL) and quenched with water (10 mL). The resulting heterogeneous mixture was
filtered, and the organic phase was separated. The organic layer was washed with saturated
aqueous NaHCO3 (20 mL), dried with Na2SO4, and filtered. The organic solvent was removed
under reduced pressure, and the residue was purified by flash column chromatography, eluting
with (EtOAc/hexanes 3:7) to afford the pure allylic alcohol 12 (719 mg) as a colorless oil in 89%
yield. [α]20D −22.70 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.38ꢀ7.22 (m, 5H), 5.60ꢀ5.49
(dt, J = 15.1 Hz, 1H), 5.39 (dd, J = 15.8 Hz, 1H), 4.85 (s, 1H), 4.69 (s, 1H), 4.46 (q, J = 12.0 Hz,
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2H), 4.21ꢀ4.05 (m, 2H), 4.02 (d, J = 6.7 Hz, 2H), 3.52ꢀ3.35 (m, 2H), 2.4 (m, 2H), 2.02 (s, 3H),
1.86 (m, 2H), 1.66 (s, 3H), 1.56ꢀ1.42 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 171.0, 143.1,
138.3, 132.6, 130.9, 128.2, 127.6, 127.4, 114.0, 72.7, 67.9, 64.5, 63.1, 49.5, 39.2, 32.0, 21.1,
20.8; IR (KBr) vmax : 3442, 3069, 3030, 2920, 2861, 1737, 1242 cmꢀ1; HRMS: Calcd for
C20H28O4Na (M+Na)+:355.1880, found: 355.1888.
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(2S,3S)ꢀ5ꢀ(Benzyloxy)ꢀ3ꢀ((2R,3R)ꢀ3ꢀ(hydroxymethyl)oxiranꢀ2ꢀyl)ꢀ2ꢀ(propꢀ1ꢀenꢀ2ꢀyl)pentyl
acetate (13)
To a stirred suspension of activated 4 Ao molecular sieves (2 g) in CH2Cl2 (12 mL) was added Dꢀ
(ꢀ)ꢀDET (0.72 mL, 4.2 mmol) and Ti(OꢀiꢀPr)4 (1.28 mL, 4.2 mmol) and the resulting mixture
was stirred for 30 min at ꢀ20 °C. The allyl alcohol 12 (700 mg, 2.1 mmol) in dry CH2Cl2 (4 mL)
was added dropwise and the resulting mixture was stirred for another 30 min at ꢀ20 °C. TBHP
(1.6 mL, 4M in toluene, 6.3 mmol) was added and the resulting mixture stirred at the same
temperature for 5 h. It was then warmed to 0 °C, quenched with TPP and stirred for 1 h at room
temperature. The resulting mixture was filtered through Celite and the filter cake was washed
well with CH2Cl2. Combined organic layers were washed with brine and dried over Na2SO4.
Removal of solvent under reduced pressure and purification by silica gel column
chromatography using ethyl acetate and hexanes (3:7) afforded 13 (600 mg, 82%) as a colorless
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viscous liquid. [α]20 +10.4 (c 2.0, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.36 ꢀ7.23 (m, 5H),
D
4.91 (s, 1H), 4.75 (s, 1H), 4.51 (s, 2H), 4.25 (dd, J = 10.9 Hz, 1H), 4.11 (dd, 1H), 3.80 (dd, J =
11.9 Hz, 3H), 3.72ꢀ3.66 (m, 1H), 3.62ꢀ3.54 (m, 2H), 2.87 (br, 1H), 2.82 (dd, J = 8.9 Hz, 1H),
2.53 (q, J = 7.9 Hz, 1H), 2.01(s, 3H), 1.96ꢀ1.89 (m, 1H), 1.79 (m, 1H), 1.71 (s, 3H), 1.56ꢀ1.49
13
(m, 1H); C NMR (CDCl3, 75 MHz): δ 170.9, 143.2, 138.3, 128.2, 127.5, 127.4, 113.9, 72.9,
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68.0, 64.0, 61.5, 58.6, 58.3, 47.3, 38.2, 30.5, 20.8; IR (KBr) vmax : 3447, 3070, 3027, 2917, 2862,
1734, 1238 cmꢀ1; HRMS: Calcd for C20H29O5 (M+H)+: 349.2010, found: 349.1991.
(2S,3S)ꢀ5ꢀ(Benzyloxy)ꢀ3ꢀ((2R,3R)ꢀ3ꢀ((tertꢀbutyldimethylsilyloxy)methyl)oxiranꢀ2ꢀyl)ꢀ2ꢀ(prop
ꢀ1ꢀenꢀ2ꢀyl)pentyl acetate (14)
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To a stirred solution of epoxy alcohol 13 (600 mg, 5.9 mmol) and imidazole (155 mg, 2.5 mmol)
in CH2Cl2 (10 mL) was added TBDMSꢀCl (336 mg, 2.2 mmol) at 0 oC portion wise over a period
of 10 min. The reaction mixture was stirred at room temperature for 2 h. The mixture was then
diluted with CH2Cl2 and washed with water and brine. The separated organic layer was dried
over anhydrous Na2SO4, and concentrated. The crude was purified by flash silica gel column
chromatography using ethyl acetate and hexanes (1:9) to afford TBS protected alcohol 14 (748
mg, 94%) as a colorless oil. [α]20D +9.4 (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.55ꢀ7.36
(m, 5H), 5.05 (s, 1H), 4.90 (s, 1H), 4.66 (s, 2H), 4.43ꢀ4.24 (m, 2H), 3.96ꢀ3.68 (m, 4H), 2.97 (m,
1H), 2.86 (dd, J = 8.87 Hz 1H), 2.68 (q, J = 7.55 Hz 1H), 2.16 (s, 3H), 2.11ꢀ1.90 (m, 2H),
1.65(m, 1H), 1.04 (s, 9H), 0.21 (m, 6H); 13C NMR (CDCl3, 75 MHz): δ 170.6, 143.1, 138.5,
128.2, 127.5, 127.3, 114.0, 72.9, 68.2, 64.2, 63.3, 58.6, 58.4, 47.4, 38.4, 30.8, 25.7, 21.1, 20.8,
18.2, ꢀ5.41, ꢀ5.49; IR (KBr) vmax : 2954, 2930, 2857, 1742, 1459, 1251, 1231 cmꢀ1; HRMS:
Calcd for C26H43O5Si : (M+H)+: 463.2874, found:463.2912.
(((2R,3R)ꢀ3ꢀ((3S,4S)ꢀ4ꢀ(Azidomethyl)ꢀ1ꢀ(benzyloxy)ꢀ5ꢀmethylhexꢀ5ꢀenꢀ3ꢀyl)oxiranꢀ2ꢀyl)
methoxy)(tertꢀbutyl)dimethylsilane (15)
To carry out the deacetylation K2CO3 (209 mg, 1.5 mmol) was added to acetate 14 (700 mg, 1.5
o
mmol) in MeOH (15 mL), and the solution was stirred for 1 h at ꢀ10 C. It was then poured in
saturated NaCl solution (5 mL), and extracted with EtOAc. Drying with (Na2SO4) and
concentration of combined organic layers in vacuo was carried out. The crude alcohol was taken
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to next step without further purification. A solution of alcohol (700 mg, 1.6 mmol) in anhydrous
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THF (7 mL) was cooled to 0 C, and triphenylphosphine (434 mg, 0.75 mmol) was added at
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once. After 5 min of stirring DIAD (330 mg, 0.33 mL, 1.6 mmol) and subsequently DPPA (440
mg, 0.36 mL, 1.6 mmol) were added. The ice bath was removed, and resulting mixture was
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stirred from 0 C, to rt for 10 h. Volatiles were evaporated under reduced pressure, and the
residue was subjected to silica gel column chromatography using ethyl acetate and hexanes (2:8)
which afforded 15 (286 mg, 45% for two steps) as a colorless viscous liquid. [α]20D −0.30 (c 1.0,
1
CHCl3); H NMR (CDCl3, 300 MHz): δ 7.38 ꢀ7.23 (m, 5H), 4.98 (s, 1H), 4.83 (s, 1H), 4.52 (s,
2H), 3.78ꢀ3.63 (m, 2H), 3.63ꢀ3.48 (m, 3H), 3.33 (dd, J = 9.8 Hz, 1H), 2.82 (m, 1H), 2.68 (dd, J =
9.06 Hz, 1H), 2.45 (m, 1H), 1.91ꢀ1.76 (m, 2H), 1.73 (s, 3H), 1.45 (m, 1H), 0.9 (s, 9H), 0.06 (s,
13
6H); C NMR (CDCl3, 75 MHz): δ 143.1, 138.3, 128.3, 127.7, 127.5, 114.8, 73.0, 63.4, 58.7,
58.3, 51.8, 48.2, 39.0, 30.9, 25.8, 20.8, ꢀ5.3, ꢀ5.4; IR (KBr) vmax : 3030, 2931, 2858, 2101, 1099
cmꢀ1; HRMS: Calcd for C24H39N3O3SiNa (M+Na)+: 468.2653, found: 468.2664.
((2R,3R)ꢀ3ꢀ((3S,4S)ꢀ4ꢀ(Azidomethyl)ꢀ1ꢀ(benzyloxy)ꢀ5ꢀmethylhexꢀ5ꢀenꢀ3ꢀyl)oxiranꢀ2ꢀyl)meꢀ
thanol (4)
To a solution of 15 (280 mg, 0.62 mmol) in THF (6 mL) was added TBAF (0.7 mL, 1.0 M in
o
THF, 0.69 mmol). The resulting solution was stirred at 0 C for 2 h and poured into saturated
NH4Cl. The mixture was extracted with EtOAc followed by drying with Na2SO4 and
concentration of combined organic layers under reduced pressure. Residue was purified by silica
gel column chromatography (hexanes/EtOAc, 7:3) to obtain 4 (187 mg, 90%) as a clear oil.
[α]20 −0.62 (c 0.8, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.39 ꢀ7.25 (m, 5H), 4.98 (s, 1H),
1
D
4.83 (s, 1H), 4.52 (s, 2H), 3.83 (br, 1H), 3.75ꢀ3.48 (m, 4H), 3.30 (dd, J = 9.0 Hz, 1H), 2.87 (m,
1H), 2.80 (dd, J = 9.0 Hz, 1H), 2.50ꢀ2.40 (m, 1H), 1.95ꢀ1.82 (m, 1H), 1.82ꢀ1.75 (m, 1H), 1.72
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(s, 3H), 1.66 (br, 1H), 1.53ꢀ1.41 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 143.5, 138.3, 128.3,
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127.6, 127.5, 114.7, 73.0, 67.9, 61.5, 58.45, 58.40, 51.6, 48.2, 38.7, 30.6, 20.3; IR (KBr) vmax
:
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3381, 3030, 2927, 2107 cmꢀ1; HRMS: Calcd for C18H25N3O3Na (M+Na)+: 354.1788, found:
354.1804.
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(2S, 3S, 4S)ꢀtertꢀButyl 3ꢀ(2ꢀ(benzyloxy)ethyl)ꢀ2ꢀ((S)ꢀ1,2ꢀdihydroxyethyl)ꢀ4ꢀ(propꢀ1ꢀenꢀ2ꢀ
yl)pyrrolidineꢀ1ꢀcarboxylate (16)
To a solution of epoxy azido alcohol 4 (100 mg, 0.30 mmol) in THF (1.5 mL) and H2O (0.2 mL)
was added triphenylphosphine (118 mg, 0.45 mmol). The reaction was stirred at room
temperature for 48 h after which tertꢀbutyl dicarbonate (98 mg, 0.1 mL, 0.45 mmol) and Et3N
were added and the stirring was continued for additional 12 h. The reaction was diluted with
EtOAc and washed with water, brine. The organic layer was dried over anhydrous Na2SO4, and
concentrated. The crude was purified by flash silica gel column chromatography using ethyl
acetate and hexanes (5:5) to afford BOC protected diol 16 (83 mg, 68%) as a clear oil. [α]20
D
−34.17 (c 2.4, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.39 ꢀ7.23 (m, 5H), 4.90 (s, 1H), 4.62 (s,
2H), 4.51 (s, 2H), 4.29 (dd, J = 4.53 Hz, 1H), 3.71ꢀ3.46 (m, 5H), 3.40ꢀ3.28 (m, 3H), 2.85 (br,
13
2H), 2.48 (m, 1H), 1.74 (s, 3H), 1.59 (m, 1H), 1.47 (s, 9H) 1.27 (m, 1H); C NMR (CDCl3, 75
MHz): δ 157.2, 141.9, 138.2, 128.3, 127.6, 127.5, 111.7, 80.7, 73.1, 72.6, 68.7, 63.8, 62.4, 47.8,
45.5, 38.9, 28.3, 27.4, 22.7; IR (KBr) vmax : 3047, 3069, 2967, 2926, 2862, 1665, 1415, 1169
cmꢀ1; HRMS: Calcd for C23H35NO5 (M+H)+: 406.2588, found: 406.2590.
(2S,3S,4S)ꢀtertꢀButyl3ꢀ(2ꢀ(benzyloxy)ethyl)ꢀ2ꢀ(hydroxymethyl)ꢀ4ꢀ(propꢀ1ꢀenꢀ2ꢀyl)pyrroꢀ
lidineꢀ1ꢀcarboxylate (17)
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To a solution of compound 16 (83 mg, 0.2 mmol) in THF/H2O (2:1, 3 mL) were added NaIO4
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(87 mg, 2 equiv, 0.4 mmol). The solution was stirred at 0 C until completion (1 h), then
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quenched by addition of H2O (5 mL) followed by the addition of CH2Cl2 (5 mL). The aqueous
layer was extracted with CH2Cl2 twice and combined organic layer were dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude aldehyde was taken to next step
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without purification. To a solution of the above aldehyde in MeOH (4 mL) at 0 C were added
NaBH4 (8 mg, 0.2 mmol). After the mixture was stirred for 10 min to complete the reaction, it
was quenched with saturated NH4Cl solution and aqueous layer was extracted with EtOAc twice.
The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography ethyl acetate and hexanes (4:6) to
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get alcohol 17 (66 mg, 87% two steps) as a clear oil. [α]20 −31.40 (c 1.0, CHCl3); H NMR
D
(CDCl3, 300 MHz): δ 7.39 ꢀ7.24 (m, 5H), 4.86 (s, 1H), 4.62 (s, 2H), 4.49 (s, 2H), 4.36 (t, J = 4.7
Hz, 1H), 3.82 (br, 1H), 3.65 (t, J = 4.7 Hz, 2H), 3.5 (br, 2H), 3.43 (d, J = 7.3 Hz, 2H), 2.78 (m,
1H), 2.1 (m, 1H), 1.69 (s, 3H), 1.60 (m, 1H), 1.47 (s, 10H); 13C NMR (CDCl3, 75 MHz): δ
157.0, 142.6, 138.2, 128.3, 127.5, 112.5, 80.4, 72.9, 68.1, 67.3, 64.7, 48.9, 46.2, 39.5, 28.4, 28.0,
22.0; IR (KBr) vmax : 3422, 3071, 2973, 2926, 2857, 1691, 1670, 1411 cmꢀ1; HRMS: Calcd for
C22H33O4NNa: (M+Na)+: 398.2302, found: 398.2296.
(2S,3S,4S)ꢀtertꢀButyl 3ꢀ(2ꢀhydroxyethyl)ꢀ2ꢀ(hydroxymethyl)ꢀ4ꢀ(propꢀ1ꢀenꢀ2ꢀyl)pyrrolidineꢀ
1ꢀcarboxylate (18)
To a solution of alcohol 17 (60 mg, 0.16 mmol) in THF (2.0 mL) at 0 oC was added a solution of
Li/naphthalene in THF (prepared by dissolving 204 mg of naphthalene in 2.0 mL of THF and
adding 8 mg of Li, stirring vigorously until a dark green solution is obtained) until the
persistence of a green color to the solution for more than 1 h. The reaction was monitored by
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TLC and complete consumption of starting material. H2O and EtOAc were added to the solution
and the phases were separated. The aqueous layer was extracted with EtOAc (3x3) and the
combined organic layers were dried on Na2SO4, filtered and concentrated. The crude product
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was purified by flash chromatography (EtOAc/Hexanes 6:4) to afford 36 mg of 18 as colorless
1
oil (81%). [α]20 −36.20 (c 0.5, CHCl3); H NMR (CDCl3, 300 MHz): δ 4.90 (s, 1H), 4.66 (s,
D
1H), 4.33 (br, 1H), 3.85ꢀ3.54 (br, 5H), 3.43 (d, J = 7.55 Hz, 2H), 2.85 (br, 1H), 2.17 (br, 1H),
1.72 (s, 3H), 1.64ꢀ1.45 (br, m, 10H), 1.36 (br, 1H); 13C NMR (CDCl3, 75 MHz): δ 156.7, 142.6,
112.5, 80.4, 66.5, 64.6, 60.7, 48.9, 46.2, 39.2, 30.6, 28.4, 22.1; IR (KBr) vmax : 3380, 2625, 2855,
1669, 1413, 772 cmꢀ1; HRMS: Calcd for C15H27NO4Na (M+Na)+: 308.1832, found: 308.1854.
(2S,3S,4S)ꢀ3ꢀ(Carboxymethyl)ꢀ4ꢀ(propꢀ1ꢀenꢀ2ꢀyl)pyrrolidineꢀ2ꢀcarboxylic acid (1)
Jones’ reagent (2.3 M, 100 ꢁL) was added drop wise over 2 min to a stirred ice cooled solution
of 18 (22 mg, 0.07 mmol) in acetone (2 mL), and stirring was continued for 30 min at 0 °C. The
overload of Jones’ reagent was quenched by addition of iꢀpropanol (200 ꢁL). The green
suspension was stirred for 5 min at 0°C and 10 min at room temperature. The clear greenish
supernatant was filtered, and the remaining green residue was extracted with EtOAc. The
combined organic layers were washed with brine dried over Na2SO4, and concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 (400 ꢁL). The solution was treated with
TFA (50 ꢁL). After stirring at room temperature for 3 h solvents were removed under reduced
pressure. The residue was dissolved in water (1 mL) and added to a column DOWEX 50 WX8
(H+) (50ꢀ100 mesh). Elution with 1M NH4OH and evaporation of the collected fractions under
reduced pressure yielded an orange oil (ꢀ)ꢀαꢀkainic acid 1 (10 mg, 62 %). [α]20 −14.3 (c 0.6,
D
1
H2O); H NMR (CDCl3, 500 MHz): δ 5.04 (s, 1H), 4.75 (s, 1H), 4.08 (s, 1H), 3.63 (dd, J =
12.1Hz, 7.6 Hz, 1H), 3.43 (t, J = 11.4 Hz, 1H), 3.09ꢀ2.97 (br, 2H), 2.36 (dd, J = 15.9 Hz, 6.0 Hz,
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1H), 2.26 (m, J = 15.9 Hz, 1H), 1.77 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 178.3, 173.6,
140.1, 113.2, 66.0, 46.4, 45.9, 41.4, 38.0, 22.3; IR (KBr) vmax : 3364, 3199, 2924, 2846, 1663,
1391, 1219 cmꢀ1; HRMS: Calcd for C10H14O4N: 212.0917, found: 212.0927.
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Acknowledgement
N.K.R. thanks UGCꢀNew Delhi, for the award of research fellowship and SCS thank CSIR New
Delhi for financial assistance.
Supporting Information
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Copies of H and C NMR spectra for all new compounds. This material is available free of
charge via the Internet at http:// pubs.acs.org.
References
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